Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

Saxena A, Little JT, Nedungadi TP, Cunningham JT. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308: H435-H446, 2015. First published December 24, 2014 doi:10.1152/ajpheart.00747.2014.-Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P Ͻ 0.05). During the normoxic dark phase in the CIH groups, only the SCMinjected group exhibited a sustained increase in MAP (P Ͻ 0.05). The AT1aR-CIH group showed significant decreases in FosB/⌬FosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/⌬FosB expression in forebrain autonomic nuclei associated with CIH. angiotensin receptor; subfornical organ; chronic intermittent hypoxia; obstructive sleep apnea; AT1aR SLEEP APNEA (SA) is increasingly being recognized as a cause of neurogenic and treatment-resistant hypertension (12,19,32,37,52). SA is associated with a sustained increase in sympathetic nerve activity (SNA) and mean arterial pressure (MAP) even during periods of wakefulness and normoxia (4, 33). Animal models of chronic intermittent hypoxia (CIH), such as the one introduced by Fletcher at al. (17), produce cardiovascular sequelae similar to sleep apnea (11). Together, it appears that CIH episodes lead to pathophysiological adaptations that may generate and sustain a heightened basal MAP, which is partially dependent on increased SNA.The renin-angiotensin system (RAS) is activated during CIH (11,16,54), and it contributes to CIH hypertension (11, 16). For example, in rats exposed to CIH, peripheral administration of losartan, an angiotensin II (ANG II) type 1 receptor (AT1R) antagonist, has been shown to prevent the increase ...

Chronic intermittent hypoxia (CIH), an animal model of hypoxemia in sleep apnea patients, increases sympathetic tone, elevates arterial pressure (AP), and increases FosB/ΔFosB staining in the organum vasculosum of the lamina terminalis (OVLT), subfornical organ, (SFO), median preoptic nucleus (MnPO), paraventricular nucleus (PVN), nucleus of the solitary tract (NTS), and rostral ventrolateral medulla (RVLM). This study tested the hypothesis that FosB/ΔFosB activity in the MnPO contributes to increased AP and activation of sympathetic control regions. Rats (n=5–6) were injected in the MnPO with a dominant negative virus expressing ΔJunD (ΔJD) to inhibit FosB/ΔFosB signaling, control vector (GFP), or not injected (CIH); these three groups were exposed to CIH for 7d in the light phase. A fourth group (CON) was neither injected nor exposed to CIH. MnPO ΔJD blocked the increase in AP during CIH. Further, MnPO ΔJD blocked increases in FosB/ΔFosB staining in the PVN (CON: 13±1 CIH: 29±3 GFP: 29±2 ΔJD: 12±2 cells/section) and RVLM (CON: 5±1 CIH: 17±2 GFP: 20±1 ΔJD: 8±2) but not the NTS (CON: 9±2 CIH: 28±4 GFP: 32±2 ΔJD:: 29±3). These data suggest that FosB/ΔFosB mediated changes in gene expression in the MnPO contribute to the increased AP and activation of the PVN and RVLM associated with CIH. CIH‐induced increases in FosB/ΔFosB along the autonomic axis may also mediate increased sympathetic tone during CIH. PO1 HL‐88052.

New Findings r What is the central question of this study?Despite the abundance of sympathetic nerve fibres emanating from the cervical and stellate ganglia that innervate the cerebral arteries, the role of the sympathetic nervous system in regulation of cerebral vasculature in humans remains equivocal. r What is the main finding and its importance?The findings from this study support the role of the sympathetic nervous system, mediated by activation of α 1 -adrenoreceptors, in dynamic cerebral autoregulation and cerebral vascular tone at rest and during moderate dynamic exercise. Blockade of the α 1 -adrenoreceptors impaired dynamic cerebral autoregulation and attenuated any increases in cerebral vascular tone during moderate dynamic exercise in healthy humans.We tested the hypothesis that pharmacological blockade of α 1 -adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 ± 0.2 to 3.2 ± 0.3 pmol (ml plasma) −1 ). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low-frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 ± 3 to 24 ± 4 to 31 ± 4 mmHg). An average of 74 ± 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 ± 0.3 to 4.4 ± 0.5 pmol (ml plasma) −1 ). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that α 1 -adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation